The overall objective of this proposal is to examine the immunogenicity of pancreatic islet tissue in vitro and in vivo relative to transplantation for amelioration of the diabetic state and to, thereby, further elucidate mechanisms in the pathogenesis of diabetes mellitus. We are developing the following in vitro assays to assess islet antigenicity: the mixed lymphocyte-islet culture (MLI) in which islets stimulate lymphocyte mitogenesis; cell-mediated cytolysis (CMC), and antibody-dependent cell-mediated cytotoxicity (ADCC) in which islets serve as targets for killer T lymphocytes. Preliminary evidence for islet antigens which appear to be different in three species (rat, dog, and human), and possibly distinct from lymphocyte alloantigens, will be explored further. Also, islets will be cultured in vitro, under different conditions, in attempts to alter islet immunogenicity, and transplantation of the cultured islets will be used to confirm the in vitro results. Islets will be implanted in the submucosa of a defunctionalized (Roux-en-Y) limb of jejunum in inbred beagle dogs (DLA identical and DLA haploidentical) made diabetic by pancreatectomy (80%) and streptozotocin. We have found this implantation site to be effective using autologous islets. The draining lymphatics of the Roux-en-Y limb of jejunum will be excised to test whether an immunologically privileged site will result. Other dogs will have an Eck fistula to determine whether drainage into the portal system lessens immunogenicity. Also, the effectiveness of implanting isolated islets in the intestinal submucosa will be compared to that of transplanting a vascularized segment of whole pancreas in the dog.